Evidence against a key role for transforming growth factor-β1 in cytomegalovirus-induced bone marrow aplasia

During immunodeficiency after sublethal haemato-ablative treatment, cytomegalovirus (CMV) infection interferes with haematopoietic reconstitution and can cause lethal bone marrow (BM) aplasia, The in vivo model of murine CMV infection has identified the BM stroma as the principal target site of CMV in the haematopoietic cord, The infected cell type is the reticular stromal cell which forms the stromal network and produces essential haemopoietins, such as stem-cell factor (SCF), The expression of SCF was found to be reduced in the infected stroma, but the stromal network was not disrupted and the number of infected stromal cells was too low to explain the functional deficiency, These facts call for a negatively regulating cytokine that is induced by the infection and that potentiates the direct effect of infection by down-regulating haemopoietins in uninfected bystander cells, Recent work has suggested that transforming growth factor (TGF)-beta 1 might be the cytokine involved in CMV-induced BM aplasia, We show here that murine CMV indirectly induces the accumulation of mature TGF-beta 1 in uninfected renal tubular epithelial cells and TGF-beta 1 transcription in BM stromal cells, whereas infected renal glomerular and interstitial cells, hepatocytes and BM stromal cells do not coexpress mature TGF-beta 1, Antiviral CD8 T-cell therapy prevented BM aplasia and also prevented the down-regulation of stromal SCF and interleukin-6 gene expression, Interestingly, however, the CD8 T cells did not preclude the up-regulation of mature TGF-beta 1, but proved to be inducers of TGF-beta 1 gene expression in BM stroma, These findings suggest that TGF-beta 1 is not the mediator of BM aplasia.